Modulation of the Antitumor Response to Metformin, Caffeine, and Sodium Dichloroacetate by the Hypoxic Microenvironment in Lung Cancer Cells
Metformin, caffeine, and dichloroacetate (DCA) have shown antitumor effects. The hypoxic tumor microenvironment can modulate drug response. We aimed to analyze the interaction of metformin with caffeine or DCA in lung cancer cells (HCC827) under normoxia and hypoxia conditions. Cell viability was evaluated using the crystal violet assay after individual and combined drug treatment under normoxia (21% O<sub>2</sub>) and hypoxia (1% O<sub>2</sub>) conditions. Combination effects were analyzed using isobolographic analysis. The results show that under normoxia conditions, the combination of metformin with DCA (γ = 0.98 ± 0.35, <i>p</i> > 0.05) or caffeine (γ = 0.90 ± 0.34, <i>p</i> > 0.05) revealed additivity. However, in hypoxia, both combinations exhibited significant antagonism, with γ values appearing greater than one for metformin + DCA (γ = 4.20 ± 1.44, <i>p</i> < 0.05) and metformin + caffeine (γ = 2.88 ± 0.90, <i>p</i> < 0.05). Hypoxia significantly alters the pharmacological interaction of metformin with caffeine or DCA, which could limit their combined therapeutic potential in hypoxic tumors despite metformin's activity in this environment. The importance of considering tumor oxygenation status in the design of combined therapies for lung cancer is emphasized.
Authors
- Heriberto Prado-Garcı́a (ORCID: https://orcid.org/0000-0002-4932-3244)
- M.O. Misael O. Garcia-Martin (ORCID: https://orcid.org/0000-0002-6725-510X)
- Juan Carlos Huerta-Cruz (ORCID: https://orcid.org/0000-0001-9006-8495)
- Ángeles Carlos‐Reyes (ORCID: https://orcid.org/0000-0002-6636-8233)
- Juan Rodríguez‐Silverio (ORCID: https://orcid.org/0000-0002-8998-1196)
- Edgar Flores‐Soto (ORCID: https://orcid.org/0000-0003-2649-8751)
- José Alberto Choreño-Parra (ORCID: https://orcid.org/0000-0002-4591-5285)
- Vı́ctor Ruiz (ORCID: https://orcid.org/0000-0003-0440-2093)
- Ana Gálvez (ORCID: https://orcid.org/0000-0003-4195-4823)
- Georgina González-Ávila (ORCID: https://orcid.org/0000-0002-3511-4265)
- Citlaltepetl Salinas‐Lara (ORCID: https://orcid.org/0000-0002-2161-6037)
- Manuel Castillejos‐López (ORCID: https://orcid.org/0000-0001-8689-9755)
- Susana Romero‐Garcia (ORCID: https://orcid.org/0000-0003-4539-0578)
- Roberto Lara‐Lemus
- Rafael Velázquez‐Cruz (ORCID: https://orcid.org/0000-0003-4515-0777)
- Yair Romero (ORCID: https://orcid.org/0000-0002-8707-025X)
- Luz María Torres‐Espíndola (ORCID: https://orcid.org/0000-0001-9929-9361)
- L.A. Colín-Godínez
- Daniel Paz-Gómez
Institutions
- National Institutes of Health (US)
- Instituto Nacional de Enfermedades Respiratorias (MX)
- National Institute of Genomic Medicine (MX)
- National Institute of Allergy and Infectious Diseases (US)
- Instituto Nacional de Pediatria (MX)
- Instituto Nacional de Neurología y Neurocirugía (MX)
- Instituto Politécnico Nacional (MX)
- Universidad Nacional Autónoma de México (MX)
Publication Details
- Journal
- International Journal of Molecular Sciences
- Published
- 2025-05-23
- DOI
- https://doi.org/10.3390/ijms26115014
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Instituto Politécnico Nacional